The goal of this proposal is to access the response rate, side effects and pharmacokinetics of a novel angiogenesis inhibitor, squalamine, when combined with a commonly used chemotherapy regimen carboplatin and paclitaxel (carbo/taxol) for advanced non-small cell lung cancer (NSCLC). Squalamine is a novel, selective inhibitor of new blood vessel formation which we have demonstrated significantly enhances the anti- tumor effects of platin compounds in our human lung cancer xenograft model. Originally identified in a screen for anti-microbial agents, it is an aminosterol that is postulated to inhibit new blood vessel growth by selectively inhibiting the sodium-hydrogen antiporter sodium-proton exchanges and inhibiting hydrogen efflux out of the endothelial cell. We examined the anti-tumor effects of squalamine with or without cytotoxic agents in human lung cancer cell lines in murine xenografts, and found that squalamine enhances the anti-tumor effects of platinum analogues in our preclinical model system by 50% to 100%. Given the significant enhancement of anti-tumor activity we observed with platin analogues in our human tumor xenograft model, and the widespread usage of carbo/taxol in the United States in advanced NSCLC, we are proposing a pilot and safety study of squalamine plus carbo/taxol in patients with Stage IIIB (pleural effusion only) and IV NSCLC. The primary objective of this study is to assess the response rate of squalamine when administered as a five-day continuous infusion in conjunction with carboplatin/taxol every three weeks. The secondary objectives are to evaluate the side effects and pharmacokinetics of squalamine when administered with these two agents. Using a two stage design, we will first establish a safe dose of squalamine that can be administered with carbo/taxol and then demonstrate that the three drug regimen is at least as efficacious as carbo/taxol alone. Once we have documented that squalamine plus carbo/taxol is safe and efficacious, we will be able to test our hypothesis that squalamine enhances time to progression and survival of advanced NSCLC patients compared to carbo/taxol alone. This will require a future randomized Phase III trial comparing carbo/taxol with and without squalamine.